Cardiovascular disease is the leading cause of death in the industrial world today. During the disease process, atherosclerotic plaques develop at various locations within the arterial system and restrict the flow of blood through the affected vessels. When such plaque develops within the blood vessels that feed the muscles and other tissues of the heart, myocardial infarctions and ischemia due to reduced blood flow to the heart tissues may result.
Over the past decades numerous devices and methods have been evaluated for preventing myocardial ischemia or cell death, including but not limited to: traditional surgical methods (e.g. open heart surgery), minimally invasive surgery, interventional cardiology (e.g. angioplasty, atherectomy, stents), and catheter based delivery of bioactive agents, including growth factors, genes and stem cells.
Open surgical methods for treating cardiovascular disease typically involve surgically accessing the heart to bypass blockages in the coronary blood vessels. Based upon the degree of coronary artery disease, a single, double, triple, or even greater number of vessels are bypassed by creating a conduit from the aorta or pedicle internal mammary artery to a stenosed coronary artery, at a location distal to the occluded site, using either synthetic or natural bypass grafts. Such procedures generally involve significant pain, extended rehabilitation time and high morbidity, and are time-consuming and costly to perform.
Minimally invasive surgical approaches have been developed wherein limited access is obtained to the heart and affected vessels using small incisions made through the ribs. While these methods reduce pain and rehabilitation time, they are available for a relatively limited number of procedures.
Interventional cardiology apparatus and methods, such as percutaneous transluminal coronary angioplasty (PTCA), rotational atherectomy, and stenting, have been developed to overcome some of the drawbacks of open and minimally-invasive surgical methods. While many patients are successfully relieved of symptoms with interventional procedures, a significant number of patients still experience irreversible myocardial injury related to abrupt closure or restenosis of the blood vessels within a relatively short period of time after the interventional procedure.
Work is currently in progress to develop advanced apparatus and methods, such as drug-coated stents, to delay or prevent restenosis. In addition, as described in Local Drug Delivery for the Treatment of Thrombus and Restenosis, IAGS Proceedings, J. Invasive Card., 8:399-408, October 1996, some practitioners augment standard catheter-based treatment techniques with devices that provide local delivery of medications to the treated site, with the goal of counteracting clotting, reducing inflammatory response, and blocking proliferative responses.
All of the foregoing methods are primarily intended to restore patency of a stenosed vessel thus improve blood flow to tissues downstream but cannot cause the muscle in the infarcted zones to regenerate. Transmyocardial revascularization was conceived as a method of supplementing the blood supply delivered to the heart by creating channels, either mechanically or by laser ablation, that extend from the endocardial surface of the left ventricle into the myocardial muscle. It was believed that such techniques could engender an angiogenic response, in which new blood vessels would form in the vicinity of the ventricular channels. The reported results for such techniques were disappointing, and such approaches have essentially been abandoned.
More recent efforts for regenerating healthy tissue in affected areas of the heart muscle involve percutaneous or direct injection of bioactive agents to the affected tissue areas, including gene vectors, growth factors, myoblasts and stem cells. For example, Mack et al., in an article entitled Biologic Bypass with the Use of Adenovirus-Medicated Gene Transfer of the Complementary Deoxyribonucleic Acid for Vascular Endothelial Growth Factor 121 Improves Myocardial Perfusion and Function in the Ischemic Porcine Heart, J. Thor. & Card. Surg. 115:168-177 (January 1998) describes experiments to improve myocardial perfusion using growth factors. Sanborn et al., Percutaneous Endocardial Gene Therapy: In Vivo Gene Transfer and Expression, J. Am. Coll. Card. 33:262A (February 1999) describe the injection of angiogenic proteins and genes directly into the heart via the endocardium using a percutaneous fluoroscopically guided system. Uchida et al., Angiogenic Therapy of Acute Myocardial Infarction by Intrapericardial Injection of Basic Fibroblast Growth Factor and Heparin Sulfate: An Experimental Study, Am. Heart J. 130:1182-1188 (December 1995), describe growth factor injections into the pericardial cavity using a catheter system inserted through the right atrium. U.S. Pat. No. 5,244,460 to Unger et al. describes a method for infusing bioactive agents containing blood vessel growth promoting peptides (i.e. fibroblast growth factor) via a catheter inserted into a coronary artery.
Thompson et al., in Percutaneous Transvenous Cellular Cardiomyoplasty, J. Am. Coll. Card., 41(11):1964-1971 (June 2003), describe apparatus and methods for pressurized injection of cultured autologous bone marrow cells, suspended in a biodegradable biogel polymer, into the myocardium using percutaneous access via the coronary sinus. An ultrasound-guided catheter was used to place a needle into a coronary vein, the needle was then extended into the myocardium, and a floppy catheter disposed within the needle was advanced into the myocardium to deliver the bone marrow cells. The article describes that the biodegradable polymer is used to reduce physical compression and lysis of the cells as they are injected into the target tissue.
U.S. patent application Publication No. US 2003/0191449 to Nash et al. describes a system for pressurized endocardial injection of bioactive materials, including growth factors, stem cells, etc., into the myocardial tissue using an endocardial approach. U.S. Pat. No. 6,432,119 to Saadat describes methods and apparatus for endocardial delivery of autologous angiogenic substances to myocardium in connection with mechanical percutaneous transmyocardial revascularization. U.S. Pat. No. 6,120,520 to Saadat et al. describes a system for providing endocardial injection of bioactive agents from a pressurized source.
As noted in the foregoing Thompson article, needle withdrawal in the preceding systems may provide an exit point for cells or gene therapy substrates to be released into systemic circulation, with a concomitant risk of embolization. In addition, pressurized injection of certain bioactive agents, such as stem cells, is expected to inflict physical damage to the cell membranes due to fluid turbulence and pressure fluctuations encountered during the injection process (referred to herein as “barotrauma”), resulting in lysis of the cells that may significantly reduce the yield of viable cells delivered at the injection site and/or trauma to the target tissue.
Further, depending upon the degree of pressure-regulation of the injection system, it may in addition be possible for some of the injected bioactive agent to be expelled from the needle track during the injection process, e.g., due to systolic muscle contraction. Forceful injection of any material into tissue also may disrupt the delicate intercellular matrix, thereby causing target tissue cellular injury. Also, if a needle were to be inadvertently inserted into a small myocardial vessel, forceful injection may result in shear stress injury to the vessel or embolization to the pulmonary artery or remote tissue.
In view of these drawbacks of previously known devices, it would be desirable to provide methods and apparatus for delivering bioactive agents, especially fragile bioactive agents, in such a way that reduces the risk of inflicting barotrauma on the bioactive agent and target tissue during delivery while at the same time minimizing the risk of embolization
It further would be desirable to provide methods and apparatus for delivering bioactive agents, especially fragile bioactive agents, that reduces the need for biodegradable carriers, such as biogels, to cushion delivery of the bioactive agents, thus reducing the risk of embolization resulting from release of such material into systemic circulation while also preserving the integrity of the target tissue.
It further would be desirable to provide methods and apparatus for delivering cells to damaged tissue to promote tissue regeneration, wherein the delivery systems and methods reduce physical trauma to the cell membranes during delivery, and enhance the proportion of viable cells delivered to the damaged tissue.